KLHL28

Summary

KLHL28 (kelch like family member 28, HGNC:19741) is a protein-coding gene on chromosome 14q21.2, encoding Kelch-like protein 28 (Q9NXS3).

Predicted to enable ubiquitin-like ligase-substrate adaptor activity. Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be part of Cul3-RING ubiquitin ligase complex. Predicted to be active in cytoplasm.

Source: NCBI Gene 54813 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 68 total
• MANE Select transcript: NM_017658

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19741
Approved symbol	KLHL28
Name	kelch like family member 28
Location	14q21.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20081
Ensembl gene	ENSG00000179454
Ensembl biotype	protein_coding
Entrez	54813

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000355081, ENST00000396128, ENST00000553817, ENST00000556239, ENST00000556500, ENST00000557468, ENST00000579157, ENST00000894795, ENST00000894796, ENST00000894797, ENST00000894798, ENST00000945246, ENST00000945247, ENST00000945248, ENST00000945249

RefSeq mRNA: 2 — MANE Select: NM_017658 NM_001308112, NM_017658

CCDS: CCDS76675, CCDS9680

Canonical transcript exons

ENST00000396128 — 5 exons

Exon	Start	End
ENSE00001428996	44934115	44934558
ENSE00001430091	44961846	44961947
ENSE00001431921	44931333	44931541
ENSE00002445140	44924324	44929191
ENSE00003755734	44945030	44945928

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 97.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.9602 / max 285.8743, expressed in 1780 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143037	18.7927	1780
143036	0.1676	63

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.46	gold quality
sperm	CL:0000019	97.17	gold quality
epithelial cell of pancreas	CL:0000083	92.30	silver quality
ileal mucosa	UBERON:0000331	91.78	gold quality
visceral pleura	UBERON:0002401	91.32	gold quality
parietal pleura	UBERON:0002400	90.11	gold quality
gingival epithelium	UBERON:0001949	89.87	gold quality
deltoid	UBERON:0001476	89.19	gold quality
tibialis anterior	UBERON:0001385	89.08	gold quality
middle temporal gyrus	UBERON:0002771	89.06	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.93	gold quality
pigmented layer of retina	UBERON:0001782	88.90	gold quality
esophagus squamous epithelium	UBERON:0006920	88.81	gold quality
endothelial cell	CL:0000115	88.77	gold quality
palpebral conjunctiva	UBERON:0001812	88.52	gold quality
mucosa of paranasal sinus	UBERON:0005030	88.25	gold quality
thymus	UBERON:0002370	87.90	gold quality
buccal mucosa cell	CL:0002336	87.80	gold quality
upper leg skin	UBERON:0004262	87.71	gold quality
gingiva	UBERON:0001828	87.66	gold quality
tibia	UBERON:0000979	87.53	gold quality
oocyte	CL:0000023	87.41	gold quality
calcaneal tendon	UBERON:0003701	87.39	gold quality
cardiac muscle of right atrium	UBERON:0003379	87.24	silver quality
bronchial epithelial cell	CL:0002328	86.87	gold quality
biceps brachii	UBERON:0001507	86.81	gold quality
vastus lateralis	UBERON:0001379	86.59	gold quality
ganglionic eminence	UBERON:0004023	86.55	gold quality
quadriceps femoris	UBERON:0001377	86.47	gold quality
germinal epithelium of ovary	UBERON:0001304	86.35	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	323.96
E-ANND-3	yes	3.70

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

270 targeting KLHL28, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6759-5P	99.99	66.54	785

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	KLHL28	ENSDARG00000101676
mus_musculus	Klhl28	ENSMUSG00000020948
rattus_norvegicus	Klhl28	ENSRNOG00000004218

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL40 (ENSG00000157119), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KBTBD3 (ENSG00000182359), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 28 — Q9NXS3 (reviewed: Q9NXS3)

Alternative names: BTB/POZ domain-containing protein 5

All UniProt accessions (6): Q9NXS3, G3V2P9, G3V4Y0, G3V5Y9, J3KNY7, J3KRJ0

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NXS3-1	1	yes
Q9NXS3-2	2

RefSeq proteins (2): NP_001295041, NP_060128* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011043	Gal_Oxase/kelch_b-propeller	Homologous_superfamily
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family

Pfam: PF00651, PF01344, PF07707

UniProt features (13 total): repeat 6, sequence conflict 3, chain 1, domain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXS3-F1	92.78	0.79

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 204 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GGGTGGRR_PAX4_03, USF_C, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, MYCMAX_01, OCT1_03, USF_01, DOUGLAS_BMI1_TARGETS_DN, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, MODULE_544, USF_02, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, CHANDRAN_METASTASIS_UP, GOBP_PROTEIN_CATABOLIC_PROCESS, GCCATNTTG_YY1_Q6

GO Biological Process (1): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), Cul3-RING ubiquitin ligase complex (GO:0031463)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

620 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL28	FBXO28	Q9NVF7	677
KLHL28	RNF166	Q96A37	676
KLHL28	DORIP1	Q4W4Y0	642
KLHL28	PRKN	O60260	553
KLHL28	TOGARAM1	Q9Y4F4	524
KLHL28	GPHA2	Q96T91	455
KLHL28	PRPF39	Q86UA1	438
KLHL28	NAA25	Q14CX7	410
KLHL28	PCNX1	Q96RV3	392
KLHL28	RSRP1	Q9BUV0	383
KLHL28	TVP23C	Q96ET8	370
KLHL28	BTBD18	B2RXH4	369
KLHL28	A0A0A6YYB9	A0A0A6YYB9	368
KLHL28	PRSS58	Q8IYP2	366
KLHL28	FKBP3	Q00688	348

IntAct

20 interactions, top by confidence:

A	B	Type	Score
PRKACB	PRKAR1A	psi-mi:“MI:0914”(association)	0.790
KLHL24	CUL3	psi-mi:“MI:0914”(association)	0.730
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CUL3	ENC1	psi-mi:“MI:0914”(association)	0.640
CUL3	RHOBTB1	psi-mi:“MI:0914”(association)	0.530
CUL3	ZSWIM8	psi-mi:“MI:0914”(association)	0.530
rep	KLHL28	psi-mi:“MI:0915”(physical association)	0.490
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
CUL3	KLHL2	psi-mi:“MI:0914”(association)	0.350
KLHL28	PRKACB	psi-mi:“MI:0914”(association)	0.350
PADI6	PER1	psi-mi:“MI:0914”(association)	0.350
PRKAR1A	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
KLHL14	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
PRKAR1B	ZNF749	psi-mi:“MI:0914”(association)	0.350
ZBTB3	AHCYL1	psi-mi:“MI:0914”(association)	0.350
KLHL28	APOA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (46): KLHL14 (Affinity Capture-MS), IPP (Affinity Capture-MS), FBXL17 (Affinity Capture-MS), KLHL21 (Affinity Capture-MS), NUDCD3 (Affinity Capture-MS), KLHL28 (Affinity Capture-MS), KLHL26 (Affinity Capture-MS), KLHL24 (Affinity Capture-MS), KLHL13 (Affinity Capture-MS), AKAP11 (Affinity Capture-MS), CUL7 (Affinity Capture-MS), PRKACB (Affinity Capture-MS), KLHL28 (Affinity Capture-RNA), KLHL26 (Affinity Capture-MS), AKAP11 (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Q1W5, B0WWP2, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, E9Q4F2, O14682, O35709, O94889, P28575, P59280, Q08BL9, Q08DK3, Q0D2A9, Q16RL8, Q1ECZ2, Q1LYM6, Q2M0J9, Q4KLM4, Q53HC5, Q56A24, Q5R7B8, Q5RGB8, Q5ZKD9, Q6DFF6, Q6DFF7, Q6TDP3, Q6TDP4, Q6TFL4, Q6V595, Q7QGL0, Q8BRG6

Diamond homologs: A0A2R8Q1W5, A9JRD8, B0WWP2, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, D3ZUU2, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, F1LZF0, F1MBP6, G3X9X1, O15062, O93567, O94889, O95198, P28575, P57790, Q04652, Q08DK3, Q13105, Q14145, Q16RL8, Q1ECZ2, Q2M0J9, Q2TBA0, Q3SWU4, Q3ZB90

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 22 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein ubiquitination	5	10.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

68 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3036 predictions. Top by Δscore:

Variant	Effect	Δscore
14:44929092:T:C	donor_gain	1.0000
14:44929202:T:C	acceptor_gain	1.0000
14:44931330:TAC:T	donor_loss	1.0000
14:44931331:ACCTG:A	donor_loss	1.0000
14:44931332:C:A	donor_loss	1.0000
14:44931537:CCACA:C	acceptor_gain	1.0000
14:44931538:CACAC:C	acceptor_gain	1.0000
14:44931540:CA:C	acceptor_gain	1.0000
14:44931542:C:CC	acceptor_gain	1.0000
14:44945925:CCAT:C	acceptor_gain	1.0000
14:44945926:CAT:C	acceptor_gain	1.0000
14:44945926:CATC:C	acceptor_gain	1.0000
14:44945927:ATC:A	acceptor_loss	1.0000
14:44945928:TC:T	acceptor_loss	1.0000
14:44945929:C:CC	acceptor_gain	1.0000
14:44945929:C:T	acceptor_loss	1.0000
14:44945930:T:A	acceptor_loss	1.0000
14:44995744:A:AG	acceptor_gain	1.0000
14:44995745:G:GA	acceptor_gain	1.0000
14:44995899:GCTG:G	donor_gain	1.0000
14:44995900:CTGG:C	donor_loss	1.0000
14:44995901:TGGTA:T	donor_loss	1.0000
14:44995902:GGTA:G	donor_loss	1.0000
14:44995903:G:GG	donor_gain	1.0000
14:44995904:T:A	donor_loss	1.0000
14:44995905:AAG:A	donor_loss	1.0000
14:44999357:CAAAA:C	acceptor_loss	1.0000
14:44999361:A:AC	acceptor_loss	1.0000
14:44999497:GGTA:G	donor_gain	1.0000
14:45006117:GGGAA:G	donor_gain	1.0000

AlphaMissense

3759 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:44931369:A:G	W506R	1.000
14:44931369:A:T	W506R	1.000
14:44929057:G:T	R563S	0.999
14:44929108:A:C	Y546D	0.999
14:44929149:C:A	G532V	0.999
14:44929149:C:T	G532D	0.999
14:44931367:C:A	W506C	0.999
14:44931367:C:G	W506C	0.999
14:44931428:C:T	G486E	0.999
14:44931478:C:A	R469S	0.999
14:44931478:C:G	R469S	0.999
14:44931479:C:A	R469M	0.999
14:44931479:C:G	R469T	0.999
14:44931508:C:A	W459C	0.999
14:44931508:C:G	W459C	0.999
14:44931510:A:G	W459R	0.999
14:44931510:A:T	W459R	0.999
14:44934139:C:T	G440E	0.999
14:44934189:T:A	R423S	0.999
14:44934189:T:G	R423S	0.999
14:44934190:C:G	R423T	0.999
14:44934219:C:A	W413C	0.999
14:44934219:C:G	W413C	0.999
14:44934221:A:G	W413R	0.999
14:44934221:A:T	W413R	0.999
14:44934527:A:G	W311R	0.999
14:44934527:A:T	W311R	0.999
14:44945060:C:T	G290E	0.999
14:44945063:C:T	G289E	0.999
14:44945156:A:G	L258P	0.999

dbSNP variants (sampled 300 via entrez): RS1000028703 (14:44932056 T>G), RS1000097293 (14:44938843 T>C), RS1000118011 (14:44953167 G>A), RS1000148447 (14:44934846 A>G), RS1000187931 (14:44951515 A>G), RS1000220859 (14:44932536 G>A), RS1000247260 (14:44932238 G>A), RS1000254155 (14:44952854 T>G), RS1000347698 (14:44946548 A>G), RS1000376650 (14:44939418 T>G), RS1000380654 (14:44963768 G>A), RS1000520823 (14:44939872 C>T), RS1000656741 (14:44939630 T>A,C), RS1000757424 (14:44957428 A>T), RS1000816678 (14:44926171 A>G)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	7
sodium arsenite	affects methylation, increases expression	2
Tobacco Smoke Pollution	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
beta-N-methylamino-L-alanine	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
testosterone undecanoate	affects cotreatment, decreases expression	1
quercitrin	increases expression	1
trichostatin A	affects expression	1
methylparaben	increases expression	1
ferrous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Amiodarone	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Copper	increases expression, affects binding	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Demecolcine	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Mercuric Chloride	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.